Centrosome instability as a mechanism to promote localized prostate cancer

项目总结/摘要 在我们的知识中有一个根本的差距来解释前列腺癌（PCa）的起源。不像许多 在癌症中，PCa在关键癌基因和肿瘤抑制基因中缺乏特征突变，相反， 显示出大规模的基因组不稳定性。我们建议研究亚细胞器的不稳定性， 这是导致前列腺上皮细胞基因组不稳定的机制。具体来说，我们专注于 在中心体上，微小的细胞质细胞器显著影响基因组的完整性。中心体可以 当它们被放大时，成为亚细胞特异性结构，正如许多不同的细胞中的情况一样。 癌症，导致有丝分裂错误，基因组不稳定性和诱导小鼠模型中的肿瘤发生。 同样地，中心体丢失导致有丝分裂错误和基因组不稳定性，与中心体相同 扩增，但尚未在癌症中报道。我们最近发现人类前列腺 腺癌缺乏中心体，为腺癌的基因组不稳定性提供了一种新的机制解释。 PCa。我们的长期目标是发现前列腺肿瘤发生的异常变化， 恶性和复发，并改善PCa的诊断和治疗策略。的目的 应用是确定中心体丢失在驱动基因组不稳定性中的作用， PCa和确定中心体消失的分子机制基础。凭借我们在 根据初步数据，我们的中心假设是，缺氧是一个关键的生理相关的决定因素， 前列腺中的中心体丢失，这反过来又刺激基因组不稳定性和肿瘤发生。的 这项研究的基本原理是解决一个具有挑衅性的问题，即癌症特异性的变化是如何在 亚细胞特异性结构（特别是中心体丢失）蒸发并导致 致癌作用这一假说将在三个具体目标进行检验：1）确定中心体丢失是否 是由前列腺细胞和肿瘤中的缺氧触发的; 2）确定中心体丢失是否驱动 正常前列腺上皮细胞中的基因组不稳定性并促进肿瘤发生;和3）确定 中心体丢失是高度前列腺上皮内瘤变（PIN，原位癌）的特征。 该方法是创新的，因为它调查了亚细胞器不稳定性的新机制 在前列腺肿瘤发生过程中：具体来说，缺氧和中心体生物发生是机械性的， 作为前列腺肿瘤形成中基因组不稳定性的驱动因素。所提出的研究是有意义的 因为它测试了一个新的概念，即一个关键的亚细胞器的丢失是导致PCa的原因。 基因组不稳定性，这既是前列腺肿瘤演变的标志，也是前列腺肿瘤演变的因素。如果我们是正确的， 中心体丢失将是人类前列腺癌发生早期的一个有形事件， 早期发现和治疗策略。

PROJECT SUMMARY/ABSTRACT There is a fundamental gap in our knowledge to explain the origin of prostate cancer (PCa). Unlike many cancers, PCa lacks signature mutations in key oncogenes and tumor-suppressor genes and, instead, displays large-scale genomic instability. We propose to study subcellular organelle instability as a mechanism that results in genomic instability in epithelial cells of the prostate gland. Specifically, we focus on centrosomes, tiny cytoplasmic organelles that dramatically influence genome integrity. Centrosomes can become subcellular pathognomonic structures when they are amplified, as is the case in many different cancers, causing mitotic errors, genomic instability and inducing tumorigenesis in mouse models. Likewise, centrosome loss causes mitotic errors and genomic instability identical to centrosome amplification, but has not been reported in cancer. We discovered recently that human prostate adenocarcinoma lack centrosomes, providing a novel mechanistic explanation for genomic instability in PCa. Our long-term goal is to discover the abnormal changes that underlie prostate tumorigenesis, malignancy and recurrence, and to improve PCa diagnosis and treatment strategies. The objective of this application is to determine the contribution of centrosome loss in driving genomic instability resulting in PCa and to determine the molecular mechanistic basis for centrosome disappearance. Drawn from our preliminary data, our central hypothesis is that hypoxia is a key physiologically-relevant determinant of centrosome loss in the prostate which, in turn, stimulates genomic instability and tumorigenesis. The rationale for the proposed research is to address the provocative question of how cancer-specific changes in subcellular pathognomonic structures (specifically, centrosome loss) transpire and contribute to carcinogenesis. This hypothesis will be tested in three specific aims: 1) Determine whether centrosome loss is triggered by hypoxia in prostate cells and tumors; 2) Determine whether centrosome loss drives genomic instability in normal prostate epithelial cells and promotes tumorigenesis; and 3) Determine if centrosome loss is characteristic of high-grade prostatic intraepithelial neoplasia (PIN, carcinoma in situ). The approach is innovative because it investigates a novel mechanism of subcellular organelle instability during prostate tumorigenesis: specifically, that hypoxia and centrosome biogenesis are mechanistically coupled as drivers of genomic instability in prostate tumor formation. The proposed research is significant because it tests a new concept that the loss of a critical subcellular organelle is responsible for PCa genomic instability, which is both a hallmark and agent of prostate tumor evolution. If we are correct, centrosome loss will be a tangible event early in the genesis of human prostate cancer, providing new early detection and treatment strategies.